The Prevention of Mother to Child Transmission (PMTCT) of HIV has made major progress in resource rich settings where transmission has been reduce to less than 2% with use of antiretroviral drugs during pregnancy and avoidance of breastfeeding. In resource limited settings where breastfeeding is crucial for infant survival, interventions are aimed at providing antiretroviral (ARV) prophylaxis during pregnancy, labor/delivery and then throughout breastfeeding. This will potentially expose the fetus and infant to as long as 24 months of antiretroviral drugs during a period of rapid brain and physical growth. Although shorter term prenatal and peripartum exposure has been found to generally safe based on studies in the US and Europe, there are concerns that longer term exposures may lead to mitochondrial dysfunction in end organs such as the brain or bone. Given that there are major plans to upscale PMTCT worldwide, it is important to carefully assess the impact of these ARV interventions on child development and growth. We propose to conduct a longitudinal cohort study to compare neurodevelopmental (ND), neurocognitive (NC), hematologic and growth outcomes of HIV and ARV exposed uninfected infants as well as their growth over 60 months and hematologic parameters; to a control group of non HIV non ARV exposed children from similar socioeconomic and cultural backgrounds. The study will co-enroll HIV ARV exposed uninfected infants from the PROMISE PMTCT trial in Blantyre Malawi and Kampala Uganda. Control healthy children matched for age, and gender will be recruited from well child and acute care clinics at the sites where the PROMISE infants have been enrolled. ND measures that have validated in these settings will be assessed at 12 and 24 months using the Mullens Test, and NC testing using the Kaufman ABC at 60 months; while neurologic status, hematologic (CDC) and growth (height, weight, head and upper mid arm circumference will be gathered annually. Maternal and caretaker education, home environment assessments will also be adjusted for in the analyses. The main independent variable of interest is duration of ARV exposure both in utero and postnatally during breastfeeding. This study will provide important data to policy makers and researchers on whether extended in utero and post partum ARV exposure among HIV and ARV exposed uninfected infants is associated with long term sequelae in terms of ND, bone marrow suppression or physical growth. This in turn will help inform PMTCT policies. PUBLIC HEALTH RELEVANCE: Narrative This prospective 5 year study will assess developmental outcomes for uninfected infants exposed to ARVs who are participating in the PROMISE clinical trial where mothers receive antiretrovirals during pregnancy and then either mothers or infants receive antiretroviral drugs through out during breastfeeding. The study will be conducted at clinical research sites in Malawi and Uganda. It will compare these neurodevelopmental test results to findings among age and gender matched children from similar cultural backgrounds but who were not exposed to antiretrovirals.